A review on the role of long non-coding RNA prostate androgen-regulated transcript 1 (PART1) in the etiology of different disorders

LncRNA prostate androgen-regulated transcript 1 (PART1) is an important lncRNA in the carcinogenesis whose role has been firstly unraveled in prostate cancer. Expression of this lncRNA is activated by androgen in prostate cancer cells. In addition, this lncRNA has a role in the pathogenesis intervertebral disc degeneration, myocardial ischemia-reperfusion injury, osteoarthritis, osteoporosis and Parkinson’s disease. Diagnostic role of PART1 has been assessed in some types of cancers. Moreover, dysregulation of PART1 expression is regarded as a prognostic factor in a variety of cancers. The current review provides a concise but comprehensive summary of the role of PART1 in different cancers and non-malignant disorders.


Introduction
Long non-coding RNAs (lncRNAs) have diverse roles in the carcinogenesis through modulation of gene expression. They can be localized in the nucleus or cytoplasm, thus regulating expression of genes through epigenetic, transcriptional and post-transcriptional mechanisms (Zhang et al., 2019a;Hussen et al., 2022). These effects are mediated through interactions with mRNAs, DNA molecules, proteins, and miRNAs (Zhang et al., 2019a;Ghafouri-Fard et al., 2022). The majority of identified lncRNAs are transcribed by RNA polymerase II; thus, they share several structural features with mRNAs, particularly in terms of having cap structure and poly A tail (Marchese et al., 2017). Yet, most lncRNAs lack coding capacity. The ENCODE project has annotated approximately 16,000 lncRNA genes in humans. These genes can produce more than 28,000 distinctive transcripts (Derrien et al., 2012).
LncRNAs have been shown to be involved in the carcinogenesis through modulation of expression of several tumor suppressor genes and oncogenes. Their altered expression in malignant cells have been associated with diverse abnormalities in the cell cycle regulation, cell proliferation, differentiation and apoptosis . During the carcinogenesis process, lncRNAs regulate cell migration, invasion and stemness, thus they have prominent roles in the metastasis .
LncRNA prostate androgen-regulated transcript 1 (PART1) is an important lncRNA in the carcinogenesis whose role has been firstly unraveled in prostate cancer. Expression of this lncRNA is activated by androgen in prostate cancer cells (Lin et al., 2000). Being encoded by a gene on gene to chromosome 5q12, PART1 has multiple alternatively transcripts none of them encoding a protein product ( Figure 1). Expression assays have revealed biased expression of PART1 in brain, prostate, salivary gland, placenta and bladder (https://www.ncbi.nlm.nih.gov/ gene/25859).
This lncRNA has dual roles in human tissues, being regarded as an oncogene in some tissues but tumor suppressor gene in others (Ran et al., 2022). The current review provides a concise but comprehensive summary of the role of PART1 in different cancers and non-malignant disorders.

Role of PART1 in cancers
Cell line studies Functional studies in a variety of cancer-derived cell lines have assessed the consequences of up-regulation or silencing of PART1. Moreover, these studies have revealed a number of PART1 counterparts. In bladder cancer cells, enhanced expression of PART1 has promoted cell proliferation and invasiveness and suppressed cell apoptosis. On the other hand, PART1 silencing has suppressed cell proliferation and invasion and promoted apoptosis . In breast cancer cells, knockdown of PART1 has led to decreased proliferation, invasion and migration. Besides, miR-4516 has been found to be a direct counterpart of PART1. Suppression of miR-4516 has been found to rescue the effects of PART1 knockdown on breast cancer cells. Therefore, PART1 binding with miR-4516 promotes development of this type of cancer . Another study in breast cancer cells has shown that PART1 silencing improves the sensitivity of these cells to cisplatin, promotes cell apoptosis, and decreases expression proteins contributing in drug resistance (Lou et al., 2020). PART1 has also been found to be is enriched in triple negative breast cancer cells and in Aldefluor high cancer stem cells. PART1 silencing in these cell lines has reduced cell proliferation, migration, and mammosphere forming ability. This lncRNA has been able to affect expression of several genes, including myosin-Va, MYO5A, zinc fingers and homeoboxes protein 2 and ZHX2. In addition, expression of miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p has been shown to be affected by PART1. PART1 has a direct interaction with miR-937-5p (Cruickshank et al., 2021). PART1 has also been among lncRNAs being targeted by the tumor suppressor protein ΔNp63α in cervical cancer cells .
In colorectal cancer cells, three independent studies have shown possible mechanisms for contribution of PART1 in the carcinogenesis. First, PART1 has been shown to regulate this process through targeting miR-150-5p/miR-520h/CTNNB1 axis and inducing activity of Wnt/β-catenin pathway (Zhou et al., 2020a). Moreover, PART1 can function as a molecular sponge for miR-143 in these cells (Hu et al., 2017). Finally, through sponging miR-150-5p, PART1 can increase expression of LRG1 in colorectal cancer cells (Lou et al., 2020).
In esophageal squamous cell carcinoma cells, PART1 has been shown to acts as a tumor suppressor lncRNA in a single study . FOXP2 has been shown to bind to the promoter region of PART1 in these cells to regulate its expression. Up-regulation of PART1 could suppress cell proliferation and invasion, while its downregulation promotes cell proliferation and invasion in esophageal squamous cell carcinoma (Figure 2). From a mechanistical point of view, PART1 functions as a molecular sponge for miR-18a-5p, leading to over-expression of SOX6 and inactivation of the βcatenin/c-myc axis . On the other hand, another study has shown that exosome-mediated transport of PART1 leads to induction of gefitinib resistance in esophageal squamous cell carcinoma cells through sponging miR-129 (Kang et al., 2018). PART1 has been shown to restrain aggressive gastric cancer via decreasing expression of PDGFB through PLZF-mediated recruitment of EZH2 (Han et al., 2020). Similarly, PART1 has a FIGURE 2 An illustration shows the different signaling pathways of PART1 lncRNA with its expression and function in different types of cancer.
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FIGURE 3
An illustration depicts the roles of PART1 activation and silencing in tumor formation in xenograft models, as well as the signaling pathways involved.
Frontiers in Cell and Developmental Biology frontiersin.org tumor suppressor role in glioma through sponging miR-190a-3p and inactivating PTEN/AKT signals (Jin et al., 2020). Moreover, it can block carcinogenic process in glioma through modulation of miR-374b/SALL1 axis (Deng et al., 2022). Tables 1, 2 summarize the results of in vitro studies that reported up-regulation and downregulation of PART1, respectively.

Animal studies
Different study groups have evaluated functional consequences of PART1 up-regulation or silencing on tumor formation in xenoraft models ( Figure 3) (Table 3). Similar to in vitro studies, both tumor suppressor role and oncogenic role have been reported  for PART1. Examples of the former type of function have been seen in animal models of cervical squamous cell carcinoma , gastric cancer (Han et al., 2020) and glioma (Deng et al., 2022) where up-regulation of PART1 has resulted in reduction of tumor growth. Animal models of colorectal carcinoma (Zhou et al., 2020a), hepatocellular carcinoma (Pu et al., 2020), lung cancer , oral squamous cell carcinoma , ovarian cancer (Li et al., 2022b) and triple negative breast cancer (Cruickshank et al., 2021).

Studies in clinical samples
Studies in clinical samples have shown up-regulation of PART1 in a variety of cancer tissues including bladder, breast and colorectal cancers (Tables 4, 5). However, there are a number of other cancerous tissues in which PART1 has been found to be down-regulated. For instance, expression of PART1 has been shown to be decreased in esophageal squamous cell carcinoma tissues parallel with down-regulation of SOX6. Notably, low expression of these two genes has been associated with TNM stage, lymph node metastasis and poor prognosis in these patients. Moreover, expression of FOXP2 has been reduced in these tissues in correlation with PART1 expression levels . However, another study in this type of cancer has revealed up-regulation of PART1 in the sera samples of gefitinib non-responders versus responders (Kang et al., 2018). Moreover, PART1 is down-regulated in cervical squamous cell carcinoma tissues . In addition, dysregulation of PART1 has been associated with TNM stage, metastasis, tumor grade and diameter as well as histological type in a variety of cancers (Tables 4, 5).

Diagnostic value of PART1
Diagnostic value of PART1 has been evaluated in the context of esophageal squamous cell carcinoma (Kang et al., 2018) and lung squamous cell carcinoma (Cao et al., 2021) (Table 6). In the former type of cancer, PART1 levels could differentiate between gefitinib responders and non-responders with AUC value of 0.839 (Kang et al., 2018). In the latter type of cancer, this lncRNA could separate cancerous and non-cancerous tissues with AUC value of 0.7857 (Cao et al., 2021).

Role of PART1 in non-malignant disorders
Cell line studies PART1 is among lncRNAs that are dysregulated in SARS-CoV-2 infected cells as revealed by an in silico analysis of GSE147507 dataset. Expression of PART1 has been found to reduced in at least two independent SARS-CoV-2-infected cell lines. Dysregulated lncRNAs have been shown to interact with a variety of genes/proteins and miRNAs which have been linked with signaling pathways regulating viral infection, inflammatory responses and immune function (Laha et al., 2021). PART1 is alos involved in the pathogenesis of intervertebral disc degeneration via regulation of the miR-93/MMP2 axis (Gao et al., 2020) as well as miR-190a-3p expression (Zhang et al., 2021a). Tables 7, 8 summarize the role of PART1 in other non-malignant disorders based on cell line studies that reported up-regulation and downregulation of PART1, respectively.

Animal studies
Two different studies in animal models have shown the importance of PART1 in myocardial ischemia-reperfusion injury (Guo et al., 2021) and Parkinson's disease (Shen et al., 2021) ( Table 9). In animal models of myocardial ischemia-reperfusion injury, up-regulation of PART1 has resulted in the alleviation of tissue injury, enhancement of cardiac function and reduction of infarction size (Guo et al., 2021).

Studies in clinical samples
Experiments in clinical samples have shown down-regulation of PART1 in biological samples obtained from patients with Alzheimer's disease (Huaying et al., 2020), Parkinson's disease (Chi et al., 2019) and preeclampsia (Peñailillo et al., 2022). On the other hand, PART1 has been found to be up-regulated in nucleus pulposus samples of patients with intervertebral disc degeneration (Gao et al., 2020). Table 10 shows the results of studies on humans samples to ascertain how PART1 is expressed in non-cancerous disorders.
Transcription of PART1 can be regulated by a number of transcription factors such as androgens, ΔNp63α, FOXP2, STAT1 and YY1. However, the importance of methylation marks in its promotor on PART1 expression has not been elucidated.
An important feature of PART1 participation in the carcinogenesis is its diverse roles and possibly its tissuedependent functions in this process. Future studies should identify the mechanism of such tissue-dependent functions and determinants its oncogenic versus tumor suppressor roles.
Since dysregulation of PART1 in tumor tissues has been associated with aggressive behavior of cancer cells, PART1 can be regarded as a prognostic factor in different types of cancers. However, data regarding the application of PART1 as a diagnostic tool in cancer is not sufficient. Since abnormal expression of PART1 has been reported in a variety of cancers, it is possible that expression levels of PART1 can differentiate cancerous tissues from normal counterparts with appropriate diagnostic power.
Taken together, PART1 participates in the pathogenesis of cancer and a variety of non-cancerous conditions including neurodegenerative disorders. Diagnostic value of PART1 has been assessed in few types of cancers, including esophageal (Kang et al., 2018) and lung (Cao et al., 2021) cancers revealing promising results. Moreover, modulation of expression of PART1 in cancer cell lines or animal models of cancers have been associated with therapeutic benefits. However, this filed lacks sufficient data from clinical models. Future functional studies can provide important information about the underlying mechanisms and consequences of PART1 dysregulation in these disorders. The results of such studies can help in design of novel therapeutic modalities based on this lncRNA, particularly in cancers.
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